Imidazole derivatives as raf kinase inhibitors

ABSTRACT

Novel compounds and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy.

This invention relates to novel compounds and their use aspharmaceuticals particularly as Raf kinase inhibitors for the treatmentof neurotraumatic diseases, cancer, chronic neurodegeneration, pain,migraine and cardiac hypertrophy.

Raf protein kinases are key components of signal transduction pathwaysby which specific extracellular stimuli elicit precise cellularresponses in mammalian cells. Activated cell surface receptors activateras/rap proteins at the inner aspect of the plasma-membrane which inturn recruit and activate Raf proteins. Activated Raf proteinsphosphorylate and activate the intracellular protein kinases MEK1 andMEK2. In turn, activated MEKs catalyse phosphorylation and activation ofp42/p44 mitogen-activated protein kinase (MAPK). A variety ofcytoplasmic and nuclear substrates of activated MAPK are known whichdirectly or indirectly contribute to the cellular response toenvironmental change. Three distinct genes have been identified inmammals that encode Raf proteins; A-Raf, B-Raf and C-Raf (also known asRaf-1) and isoformic variants that result from differential splicing ofmRNA are known.

Inhibitors of Raf kinases have been suggested for use in disruption oftumor cell growth and hence in the treatment of cancers, e.g.histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer andpancreatic and breast carcinoma; also in the treatment and/orprophylaxis of disorders associated with neuronal degeneration resultingfrom ischemic events, including cerebral ischemia after cardiac arrest,stroke and multi-infarct dementia and also after cerebral ischemicevents such as those resulting from head injury, surgery and/or duringchildbirth; also in chronic neurodegeneration such as Alzheimer'sdisease and Parkinson's disease; also in the treatment of pain, migraineand cardiac hypertrophy.

We have now found a group of novel compounds that are inhibitors of Rafkinases, in particular inhibitors of B-Raf kinase.

According to the invention there is provided a compound of formula (I):

wherein

X is O, CH₂, CO, S or NH, or the moiety X—R¹ is hydrogen;

Y₁ and Y₂ are independently N or CH;

R¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₆alkyl,heterocyclyl, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl,any of which may be optionally substituted; in addition when X is CH₂then R¹ may be hydroxy or C₁₋₆alkoxy which may be optionallysubstituted;

R² is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl,heterocyclyl, aryl or heteroaryl, any of which may be optionallysubstituted;

Ar is a group of the formula a) or b):

wherein A represents a fused 5- to 7-membered ring optionally containingup to two heteroatoms selected from O, S and NR⁵, wherein R⁵ is hydrogenor C₁₋₆alkyl, which ring is optionally substituted by up to 2substituents selected from halogen, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy orketo;

R³ and R⁴ are independently selected from hydrogen, halogen, C₁₋₆alkyl,aryl, aryl C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, haloC₁₋₆alkyl,arylC₁₋₆alkoxy, hydroxy, nitro, cyano, azido, amino, mono- anddi-N—C₁₋₆alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy,carboxy salts, carboxy esters, carbamoyl, mono- anddi-N—C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino,sulphonylamino, aminosulphonyl, C₁₋₆alkylthio, C₁₋₆alkylsulphinyl orC₁₋₆alkylsulphonyl;

R¹⁵ is O or N—OH;

one of X₁ and X₂ is N and the other is NR⁶ wherein R⁶ is hydrogen orC₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof

As used herein, the double bond indicated by the dotted lines of formula(I), represent the possible tautomeric ring forms of the compoundsfalling within the scope of this invention. It will be understood thatthe double bond is to the unsubstituted nitrogen.

The oxime moiety can be positioned on any of carbon atoms of thenon-aromatic ring in groups a) and b).

Alkyl and alkenyl groups referred to herein, individually or as part oflarger groups e.g. alkoxy, may be straight or branched groups containingup to six carbon atoms.

Cycloalkyl and cycloalkenyl groups referred to herein include groupshaving from three to seven and five to seven ring carbon atomsrespectively.

Optional substituents for alkyl, alkenyl, cycloalkyl and cycloalkenylgroups include aryl, heteroaryl, heterocyclyl, C₁₋₆alkoxy,C₁₋₆alkylthio, arylC₁₋₆alkoxy, aryl C₁₋₆alkylthio, amino, mono- ordi-C₁₋₆alkylamino, aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy andesters thereof, amide, ureido, guanidino, C₁₋₆alkylguanidino, amidino,C₁₋₆alkylamidino, C₁₋₆acyloxy, hydroxy, and halogen or any combinationsthereof. A further substituent can be cyano.

Preferably the optional substituent contains a water-solubilising group;suitable solubilising moieties will be apparent to those skilled in theart and include hydroxy and amino group. Even more preferably theoptional substituent includes amino, mono or di-C₁₋₆alkyl, amino, aminocontaining heterocyclyl or hydroxy or any combination thereof.

When used herein, the term “aryl” means single and fused rings suitablycontaining from 4 to 7, preferably 5 or 6, ring atoms in each ring,which rings, may each be unsubstituted or substituted by, for example,up to three substituents. A fused ring system may include aliphaticrings and need include only one aromatic ring. Suitable aryl groupsinclude phenyl and naphthyl such as 1-naphthyl or 2-naphthyl.

When used herein the term “heterocyclyl” suitably includes, unlessotherwise defined, non-aromatic, saturated or unsaturated, single andfused, rings suitably containing up to four heteroatoms in either orboth rings, each of which is selected from O, N and S, which rings, maybe unsubstituted or substituted by, for example, up to threesubstituents. Each heterocyclic ring suitably has from 4 to 7,preferably 5 or 6, ring atoms. A fused heterocyclic ring system mayinclude carbocyclic rings and need include only one heterocyclic ring.Examples of heterocyclyl groups include pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, imidazolidine and pyrazolidine.Prefered examples of heterocyclyl groups include pyrrolidine,piperidine, piperazine, morpholine, imidazolidine and pyrazolidine.

When used herein, the term “heteroaryl” suitably includes, unlessotherwise defined, mono- and bicyclic heteroaromatic ring systemscomprising up to four, preferably 1 or 2, heteroatoms each selected fromO, N and S. Each ring may have from 4 to 7, preferably 5 or 6, ringatoms. A bicyclic heteroaromatic ring system may include a carbocyclicring. Examples of heteroaryl groups include pyrrole, quinoline,isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole,triazole, imidazole and benzimidazole.

Suitably aryl, heterocyclyl and heteroaryl groups may be optionallysubstituted by preferably up to three substituents. Suitablesubstituents include halogen, hydroxy, C₁₋₆alkyl, aryl, arylC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, haloC₁₋₆alkyl, arylC₁₋₆alkoxy, nitro,cyano, azido, amino, mono- and di-N—C₁₋₆alkylamino, acylamino,arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters,carbamoyl, mono- and di-N—C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonyl,aryloxycarbonyl, ureido, guanidino, C₁₋₆alkylguanidino, amidino,C₁₋₆alkylamidino, urea, carbamate, acyl, sulphonylamino, aminosulphonyl,C₁₋₆alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆alkylsulphonyl, heterocyclyl,heteroaryl, heterocyclylC₁₋₆alkyl and heteroaryl C₁₋₆alkyl, or anycombination thereof. In addition two ring carbon atoms may be linked toform a bicyclic system.

When used herein halogen means fluoro, chloro, bromo or iodo.

In the compounds of formula (I):

X is preferably O, CH₂, S or NH, or the moiety X—R¹ is hydrogen.

More preferably X is CH₂ or NH or X—R¹ is hydrogen, most preferably X isNH or X—R¹ is hydrogen.

Preferably Y₁ is CH and Y₂ is N or CH.

Preferably R¹⁵ is N—OH.

Alternatively, R¹ is hydrogen, C₁₋₆alkyl, aryl, arylC₁₋₆alkyl,heterocyclyl, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl,any of which may be optionally substituted; in addition when X is CH₂then R¹ may be hydroxy or C₁₋₆alkoxy which may be optionallysubstituted.

R² can be C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl orheterocyclyl, any of which may be optionally substituted. AlternativelyR² is aryl or heteroaryl, either of which may be optionally substituted.

Preferably Ar is a group Ar is a group of the formula a) or b):

R⁴ is as defined for compounds of formula (I), n is 1, 2 or 3 and R¹⁵ isO or N—OH.

More preferably Ar is a group of formula a) or b)

wherein R⁴ is as defined for compounds of formula (I), and n is 1, 2 or3.

n is preferably 1.

Ar is preferably an indone group

Suitable optional substituents for the group R² include one or moregroups selected from the group consisting of aryl, heteroaryl,heterocyclyl, C₁₋₆alkoxy, C₁₋₆alkylthio, arylC₁₋₆alkoxy,arylC₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino, aminosulphonyl,cycloalkyl, cycloalkenyl, carboxy and esters thereof, amide, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino, C₁₋₆acyloxy,hydroxy, and halogen or any combinations thereof. Alternatively thesubstituent can be C₁₋₆alkylaryl

R² is preferably a group that contains a solubilising moiety, suitablesolubilising moieties will be apparent to those skilled in the art andinclude basic groups. Particular solubilising groups that can bementioned include amine and hydroxy groups. For example, amino, mono- ordi-C₁₋₆alkylamino, amine containing heterocyclyl or hydroxy groups orany combination thereof.

Specific R² groups that may be mentioned include —CR⁷R⁸—CH₂-Z, —CH₂-Zand heterocyclyl, wherein R⁷ and R⁸ independently represent optionallysubstituted C₁₋₆alkyl, or R⁷ and R⁸ together with the carbon atom towhich they are attached form an optionally substituted C₃₋₇cycloalkyl orC₅₋₇cycloalkenyl ring; and Z is NR⁹R¹⁰, NR⁹C(Q)NR⁹R¹⁰, NR⁹COOR¹⁰,NR⁹SO₂R¹⁰, NR⁹C(Q)R¹⁰ or heterocyclyl wherein R⁹ and R¹⁰ areindependently selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,heterocyclyl, heterocyclylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heteroaryl andheteroarylC₁₋₆alkyl, any of which may be optionally substituted ortogether form a heterocyclic group, when present as NR⁹R¹⁰; Q is O or S,preferably O; and when R² or Z is heterocyclyl, e.g. piperidyl,piperazine or morpholine, the heterocyclyl group is optionallysubstituted.

Specific R² groups that may be mentioned include optionally substitutedphenyl, pyridyl, pyrimidyl and furanyl.

Further specific R² groups which may be mentioned included phenylsubstituted by a group —O—(CH₂)_(m)—NR¹⁸R¹⁹ or —(CH₂)_(m)—NR¹⁸R¹⁹,wherein m is an integer from 1 to 6, e.g. 2 or 3, and R¹⁸ and R¹⁹independently represent hydrogen, C₁₋₆alkyl, or R¹⁸ and R¹⁹ togetherwith the nitrogen atom to which they are attached form an optionallysubstituted 5- to 7-membered ring optionally containing an additionalheteroatom selected from NR²⁰ and O, wherein R²⁰ is hydrogen orC₁₋₆alkyl, e.g. morpholinyl.

Alternatively R⁷ or R⁸ can be hydrogen.

R³ is preferably hydrogen.

R⁴ is preferably hydrogen.

R⁶ is preferably hydrogen.

The compounds of formula (I) preferably have a molecular weight of lessthan 800.

It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded within the scope of the invention.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts. As usedherein “pharmaceutically acceptable derivatives” includes anypharmaceutically acceptable salt, ester or salt of such ester of acompound of formula (I) which, upon administration to the recipient, iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

Preferably the derivative is a salt

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts.

It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Other salts e.g. oxalates, may be used, for example in the isolation ofcompounds of formula (I) and are included within the scope of thisinvention.

The compounds of this invention may be in crystalline or non-crystallineform, and, if crystalline, may optionally be hydrated or solvated. Thisinvention includes within its scope stoichiometric hydrates as well ascompounds containing variable amounts of water.

The invention extends to all isomeric forms including stereoisomers andgeometric isomers of the compounds of formula (I) including enantiomersand mixtures thereof e.g. racemates. The different isomeric forms may beseparated or resolved one from the other by conventional methods, or anygiven isomer may be obtained by conventional synthetic methods or bystereospecific or asymmetric syntheses.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

Compounds of formula (I) are imidazole derivatives which may be readilyprepared using procedures well-known to those skilled in the art, anddescribed in, for instance, Comprehensive Heterocyclic Chemistry,Editors Katritzky and Rees, Pergamon Press, 1984, 5, 457-497, fromstarting materials which are either commercially available or can beprepared from such by analogy with well-known processes.

Examples of processes for preparing compounds of this invention are asoutlined in schemes 1 and 2. The schemes illustrate the production ofcompounds in which —X—R¹, R³ and R⁴ are hydrogen, X₁ is NH, Y₁ and Y₂are CH and Ar is a group of formula a) wherein n is 1, however theprocesses are applicable for the production of all the compounds offormula (I). In the first such process (scheme 1), α-diketones areprepared by reaction of the anion of an O-protected derivative of4-pyridine-methanol, with a suitably protected fused bicyclicaryl-aldehyde wherein PG is an oxime protecting group e.g. ═N—OR¹¹wherein R¹¹ is optionally substituted C₁₋₆ alkyl, e.g. methyl,optionally substituted aryl or silyl, or PG is a ketone protectinggroup. O-deprotection followed by oxidation of the intermediate diolaffords the aforementioned α-diketones. Reacting the diketone with asuitable aldehyde and ammonium acetate in a solvent e.g. acetic acid,methoxy^(t)butylether, or methanol, allows access to the imidazolenucleus. Thereafter, the group R² may be converted into another groupR², using conventional functional group interconversion procedures, andthe group PG converted into an oximino group (═N—OH).

The second such process (scheme 2) is analogous to that described byLiverton et al (J. Med. Chem., 1999, 42, 2180). In this approach,2-bromo-1-pyridine-4-yl-ethanone is reacted with a suitable amidine toform the central imidazole nucleus. Protection of the labile imidazolehydrogen (typical protecting groups, PG,′ are2-trimethylsilyl-ethoxymethyl-, SEM, and methoxymethyl-, MOM) thenallows metallation of the imidazole ring. Introduction of the remainingsubstituent can then be achieved by a transition metal catalysedcross-coupling of the metallated imidazole with a suitably protected,fused bicyclic aromatic system substituted with a halogen or sulphonateester, wherein PG is ═O or a protecting group as defined for Scheme 1above. Such transition metal coupling procedures are well known to thoseskilled in the art and described in, for instance, D. W. Knight inComprehensive Organic Synthesis, volume 4, page 481, editors B. M. Trostand I. Fleming, Pergamon Press, 1991. Thereafter, the group R² may beconverted into another group R², using conventional functional groupinterconversion procedures, the protecting group PG′ removed and thegroup PG converted into an oximino group (═N—OH). It will also beappreciated that the cross-coupling procedure could be reversed suchthat a halogenated imidazole is coupled with a suitably protected,metallated fused bicyclic aromatic system

Compounds of formula (I) wherein R⁶ is C₁₋₆ alkyl may be produced byalkylation of a compound of formula (II), following removal of theprotecting group PG′, by a process analogous to that described byLiverton et al (J. Med. Chem., 1999, 42, 2180). The resulting isomersmay be separated by chromatographic techniques.

During the synthesis of the compounds of formula (I) labile functionalgroups in the intermediate compounds, e.g. hydroxy, carboxy and aminogroups, may be protected. A comprehensive discussion of the ways inwhich various labile functional groups may be protected and methods forcleaving the resulting protected derivatives is given in for exampleProtective Groups in Organic Chemistry, T. W. Greene and P. G. M. Wuts,(Wiley-Interscience, New York, 2nd edition, 1991).

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I), orpharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

Various of the intermediates used in the production of the compounds offormula (I) are novel thus according to a further aspect of theinvention there is provided a compound of formula (II), (III) or (IV),wherein PG represents ═O or a protecting group and PG′ represents aprotecting group. Suitable protecting groups include those describedabove.

As indicated above the compounds of formula (I) and theirpharmaceutically acceptable derivatives are useful for the treatmentand/or prophylaxis of disorders in which Raf kinases, in particularB-Raf kinase, are implicated.

According to a further aspect of the invention there is provided the useof a compound of formula (I) or a pharmaceutically acceptablederivatives thereof as an inhibitor of B-Raf kinase.

As indicated above the compounds of formula (I) and theirpharmaceutically acceptable derivatives are useful for the treatmentand/or prophylaxis of disorders associated with neuronal degenerationresulting from ischemic events, as well as chronic neurodegeneration,pain, migraine and cardiac hypertrophy.

According to a further aspect of the invention there is provided amethod of treatment or prophylaxis of a neurotraumatic disease, in amammal in need thereof, which comprises administering to said mammal aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

According to a further aspect of the invention there is provided the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof in the manufacture of a medicament for the prophylactic ortherapeutic treatment of any disease state in a human, or other mammal,which is exacerbated or caused by a neurotraumatic event.

Neurotraumatic diseases/events as defined herein include both open orpenetrating head trauma, such as caused by surgery, or a closed headtrauma injury, such as caused by an injury to the head region. Alsoincluded within this definition is ischemic stroke, particularly to thebrain area, transient ischemic attacks following coronary by-pass andcognitive decline following other transient ischemic conditions.

Ischemic stroke may be defined as a focal neurologic disorder thatresults from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. Roles for stress stimuli (such as anoxia),redox injury, excessive neuronal excitatory stimulation and inflammatorycytokines in this area has been emerging and the present inventionprovides a means for the potential treatment of these injuries.Relatively little treatment, for an acute injury such as these has beenavailable.

The compounds of the invention may also be used in the treatment orprophylaxis of cancers.

According to a further aspect of the invention there is provided amethod of treatment or prophylaxis of a cancer, in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablederivative thereof.

According to a further aspect of the invention there is provided the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof in the manufacture of a medicament for the prophylactic ortherapeutic treatment of cancer.

According to a further aspect of the invention there is provided amethod of treatment or prophylaxis of a chronic neurogeneration, pain,migraine and cardiac hypertrophy, in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof formula (I) or a pharmaceutically acceptable derivative thereof.

According to a further aspect of the invention there is provided the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof in the manufacture of a medicament for the prophylactic ortherapeutic treatment of chronic neurogeneration, pain, migraine andcardiac hypertrophy.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice.

According to a further aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable derivative thereof and a pharmaceuticallyacceptable carrier.

The compounds of formula (I) may conveniently be administered by any ofthe routes conventionally used for drug administration, for instance,parenterally, orally, topically or by inhalation. The compounds offormula (I) may be administered in conventional dosage forms prepared bycombining it with standard pharmaceutical carriers according toconventional procedures. The compounds of formula (I) may also beadministered in conventional dosages in combination with a known, secondtherapeutically active compound. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation. It will be appreciated that the form andcharacter of the pharmaceutically acceptable carrier is dictated by theamount of compound of formula (I) with which it is to be combined, theroute of administration and other well-known variables. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule or nonaqueousliquid suspension.

The compounds of formula (I) are preferably administered parenterally,that is by intravenous, intramuscular, subcutaneous, sublinqual,intranasal, intrarectal, intravaginal or intraperitoneal administration.The intravenous form of parenteral administration is generallypreferred. The compounds may be administered as a bolus or continuousinfusion e.g. for 6 hours up to 3 days. Appropriate dosage forms forsuch administration may be prepared by conventional techniques.

The compounds of formula (I) may also be administered orally.Appropriate dosage forms for such administration may be prepared byconventional techniques.

The compounds of formula (I) may also be administered by inhalation,that is by intranasal and oral inhalation administration. Appropriatedosage forms for such administration, such as aerosol formulations, maybe prepared by conventional techniques.

The compounds of formula (I) may also be administered topically, that isby non-systemic administration. This includes the application of theinhibitors externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream.

For all methods of use disclosed herein the daily oral dosage regimenwill preferably be from about 0.1 to about 200 mg/kg of total bodyweight, preferably from about 0.2 to 30 mg/kg, more preferably fromabout 0.5 to 15 mg/kg. The daily parenteral dosage regimen about 0.1 toabout 200 mg/kg of total body weight, preferably from about 0.2 to about30 mg/kg, and more preferably from about 0.5 to 15 mg/kg. The dailytopical dosage regimen will preferably be from 0.1 mg to 150 mg,administered one to four, preferably two or three times daily. The dailyinhalation dosage regimen will preferably be from about 0.01 mg/kg toabout 1 mg/kg per day. It will also be recognized by one of skill in theart that the optimal quantity and spacing of individual dosages of theinhibitors will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular patient being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of the inhibitors given per day for a defined number ofdays, can be ascertained by those skilled in the art using conventionalcourse of treatment determination tests. In the case of pharmaceuticallyacceptable salts the above figures are calculated as the parent compoundof formula (I).

No toxicological effects are indicated/expected when a compound offormula (I) is administered in the above mentioned dosage range.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention.

The abbreviations used herein are as follows:

THF means tetrahydrofuran

DMF means N,N-Dimethylforamide

TBAF means tetrabutylammonium fluoride

DMSO means dimethylsulfoxide

LDA means lithium diisopropyl amide

EXAMPLE 15-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

Step 1: 5-Bromo-indan-1-one O-methyl-oxime

To a solution of 5-bromo-indanone (100 g, 0.474 mol) in ethanol (650 ml)under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) andpyridine (125 ml). The mixture was refluxed for 2.5 hours, cooled toroom temperature and poured into saturated aqueous sodium hydrogencarbonate solution. The mixture was then extracted with ethyl acetateand the organic phase dried (Na₂SO₄) and then concentrated in vacuo. Thecrude material was recrystallised from isopropanol to furnish the titlecompound, (110 g, 97%), as a brown solid; ¹H NMR (CDCl₃) 7.52 (1H, d, J8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz), 3.97 (3H, s),2.99 (2H, m), 2.99 (2H, m), 2.85 (2H, m).

Step 2: 1-Methoxyimino-indan-5-carbaldehyde

To a solution of the product of Step 1 (112 g, 0.46 mol) in THF (1500ml) at −60° C. under argon, was added n-BuLi (325 ml, 0.52 mol) over 1hour. After stirring at −60° C. for 1 hour a solution of DMF (39.7 ml)in THF (50 ml) was added dropwise over 1 hour. The reaction was stirredat −60° C. for 1 hour before being allowed to warm to room temperature.After 1 hour the reaction was quenched with saturated aqueous sodiumhydrogen carbonate solution and extracted into ethyl acetate. Theorganic phase was then dried (Na₂SO₄), concentrated in vacuo and theresidue purified by silica gel chromatography, to give the titlecompound (57 g, 65%) as a yellow solid; ¹H NMR (CDCl₃) 10.0 (1H, s),7.83-7.73 (3H, m), 4.02 (3H, s), 3.10 (2H, m), 2.92 (2H, m).

Step 3:5-(1,2-Dihydroxy-2-pyridin-4-yl-ethyl)-indan-1-one-O-methyl-oxime

To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine [T.F. Gallagher et al, Bioorg. Med. Chem., 1997, 5, 49] (71.5 g, 0.32 mol)in THF (800 ml) at −50° C. under argon was added LDA (162 ml, 2M inheptane/THF/ethylbenzene, 0.324 mol) over 1 hour. The mixture wasstirred at −40° C. for a further 1 hour before a solution of the productof Step 2 (55 g, 0.29 mol) in THF (600 ml) was added over 1 hour. Thereaction was then allowed to warm to room temperature overnight beforebeing quenched by the addition of saturated aqueous sodium hydrogencarbonate solution and then extracted into ethyl acetate. The organicphase was dried (Na₂SO₄) and concentrated in vacuo to give a brown oil(125 g).

The oil was then dissolved in THF (1500 ml), treated with TBAF (356 ml,0.356 mol) and stirred for 1 hour. The reaction mixture was thenevaporated and the residue partitioned between water and ethyl acetate.The organic phase was then dried (Na₂SO₄) and concentrated to give thetitle compound (57 g, 64%) as a pale yellow solid which was used withoutfurther purification. ¹H NMR (CDCl₃) 8.38 (2H, m), 7.57 (1H, m),7.12-6.99 (4H, m), 4.88 (1H, m), 4.66 (1H, m), 3.96 (3H, s), 2.93 (2H,m), 2.85 (2H, m).

Step 4: 1-(1-Methoxyimino-indan-5-yl)-2-pyridin-4-yl-ethane-1,2-dione

To a mixture of DMSO (43 ml, 0.56 mol) and dichloromethane (800 ml) at−70° C. under argon, was added oxalyl chloride (71.4 g) and then asolution of the product of Step 3 (55 g, 0.185 mol) in a mixture ofdichloromethane/DMSO (1000 ml/60 ml) over 2 hours at −60° C. Afterstirring for 2 hours at −60° C., triethylamine (154 ml) was addeddropwise and the mixture then allowed to warm to room temperatureovernight. The reaction mixture was then quenched with water, theorganic phase separated then washed with water, dried (Na₂SO₄) andconcentrated to yield the title compound (51 g, 94%) as a yellow solid.¹H NMR (CDCl₃) 8.87 (2H, d), 7.89-7.77 (5H, m), 4.03 (3H, s), 3.09 (2H,m), 2.93 (2H, m).

Step 5:{2-[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-carbamicacid tert-butyl ester

A mixture of the product of Step 4 (1.02 g, 3.47 mmol),(2,2-dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester (0.84 g, 4.16mmol) [Y. Guindon et al, J. Am. Chem. Soc., 1997, 119, 9289] andammonium acetate (1.34 g, 17.4 mmol) in MeOH (15 ml) and tert-butylmethyl ether (30 ml) was stirred at room temperature for 2 hours. Thereaction was then poured into water and extracted with ethyl acetate.The organic extract was then dried (MgSO₄), concentrated in vacuo andthe crude material purified by silica gel chromatography eluting withethyl acetate to give the title compound (0.450 g, 27%) as a colourlesssolid; MS(AP+) m/e 477 [M+H]⁺

Step 6:5-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-one

A mixture of the product of Step 5 (0.400 g, 0.839 mmol) and 5M HCl (2ml) in dioxan (4 ml) was heated to 100° C. for 1 hour. Acetone (10drops) was then added and the heating continued for a further 1 hourbefore the mixture was cooled to room temperature and reduced in vacuo.The residue was purified by silica gel chromatography, eluting with a2:18:80 mixture of 0.88 ammonia solution:methanol:ethyl acetate to givethe title compound (0.18 g, 62%) as a yellow solid; MS(AP+) m/e 348[M+H]⁺.

Step 7:5-[2-(2-Amino-1,1-dimethyl-ethyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

To a solution of the product of Step 6 (0.12 g, 0.350 mmol) in ethanol(5 ml) at 80° C. was added aqueous hydroxylamine (0.07 g, 1.04 mmol, 50%in water). After 30 min the mixture was cooled to room temperature andconcentrated in vacuo to give the title compound, (0.124 g, 100%) as ayellow solid; MS(AP+) m/e 362 [M+H]⁺.

EXAMPLE 2N-{2-[5-(1-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-methanesulfonamide

Step 1:N-{2-Methyl-2-[5-(1-oxo-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-propyl}-methanesulfonamide

A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol ) andmethane sulphonyl chloride (0.023 ml, 0.3 mmol) in dichloromethane (3ml) was stirred at room temperature for 2 hours. The reaction was thenpoured into ethyl acetate, washed with water and aqueous sodium hydrogencarbonate solution, dried (MgSO₄) and concentrated in vacuo. The cruderesidue was then purified by silica gel chromatography eluting with a1:9:90 mixture of 0.88 ammonia solution:methanol:dichloromethane to givethe title compound (0.075 g, 61%) as a yellow solid; MS(AP+) m/e 425[M+H]⁺.

Step 2:N-{2-[5-(1-Hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-methanesulfonamide

The title compound (0.06 g, 90%) was prepared from the product of Step 1as described in Example 1 Step 7; MS(AP+) m/e 440[M+H]⁺.

EXAMPLE 3 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide

Step 1: 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid{2-methyl-2-[5-(1-oxo-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-propyl}-amide

A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol),1-hydroxybenzo-triazole (0.06 g, 0.44 mmol) and polymer bound1,3-dicyclohexylcarbodiimide (0.4 g, 0.6 mmol, 1.52 mmol/g) in a 1:1mixture of dichloromethane and DMF (4 ml) was stirred at roomtemperature for 30 min. A solution of1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO97/25309] (0.098 g, 0.44 mmol) in DMF (2 ml) was then added and themixture stirred at room temperature overnight. The reaction mixture wasthen filtered, the solvent removed in vacuo and the crude residuepurified by silica gel chromatography eluting with a 1:9:90 mixture of0.88 ammonia solution:methanol:dichloromethane to give the titlecompound (0.12 g, 80%) as a yellow oil; MS(AP+) m/e 516 [M+H]⁺.

Step 2: 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide

The title compound (0.07 g, 70%) was prepared from the product of Step 1as described in Example 1 Step 7; MS(AP+) m/e 531[M+H]⁺.

EXAMPLE 45-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime

Step 1.4-[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (0.765 g, 79%) was prepared from the product ofExample 1 Step 4 and 4-formyl-piperidine-1-carboxylic acid tert-butylester (S. I. Klein et al; J. Med. Chem., 1998, 41, 2492) as described inExample 1 Step 5; MS(AP+) m/e 488 [M+H]⁺.

Step 2. 5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

The title compound (0.55 g, 90%) was prepared from the product of Step 1as described in Example 1 Step 6; MS(AP+) m/e 359 [M+H]⁺.

Step 3. 5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

The title compound (0.35 g, 90%) was prepared from the product of Step 2as described in Example 1 Step 7 followed by purification by silica gelchromatography eluting with 0.88 ammoniasolution:methanol:dichloromethane mixtures. MS(AP+) m/e 374 [M+H]⁺.

EXAMPLE 55-[2-(1-{1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-mathanoyl}-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

The title compound (0.028 g, 28%) was prepared from the product ofExample 4 and 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acidhydrochloride [WO 97/25309] as described in Example 3 Step 1; MS(AP+)m/e 543 [M+H]⁺.

EXAMPLE 65-[2-(1-Furan-3-ylmethyl-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

A mixture of the product of Example 4 (0.093 g, 0.25 mmol),3-furaldehyde (0.024 g, 0.25 mmol) and polymer bound trimethylammoniumcyanoborohydride (0.125 g, 0.5 mmol, 4 mmol/g) in methanol (3 ml)containing acetic acid (0.1 ml) was stirred at room temperature for 24hours. The reaction mixture was poured onto the top of an SCX columneluting with 0.880 ammonia solution:methanol mixtures (0-10%), theproduct was then purified further by silica gel chromatography elutingwith a 1:9:90 mixture of 0.880 ammonia solution:ethanol:dichloromethaneto give the title compound (0.070 g, 62%) as a solid; MS(AP+) m/e 454[M+H]⁺.

EXAMPLE 75-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

Step 1. 1-(2-Methoxy-ethyl)-piperidine-4-carbaldehyde

To a solution of 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethylester [WO97/25309] (2.0 g, 9.3 mmol) in toluene (40 ml) at −78° C. wasadded diisobutylaluminum hydride (10.2 ml, 1M solution intetrahydrofuran, 10.2 mmol) over 1 hour. After 1 hour the reactionmixture was quenched with methanol (5 ml) and saturated ammonium acetatesolution (5 ml). The mixture was stirred at room temperature for 1 hourand then filtered. The filtrate was concentrated to give the titlecompound as a yellow oil (1.1 g, 69%); MS(AP+) m/e 172 [M+H]⁺.

Step 2.5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneO-methyl-oxime

The title compound (0.27 g, 32%) was prepared from the product of Step 1and the product of Example 1 Step 4 as described in Example 1 Step 5;MS(AP+) m/e 446 [M+H]⁺.

Step 3.5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one

The title compound (0.193 g, 93%) was prepared from the product of Step2 as described in Example 1 Step 6; MS(AP+) m/e 417 [M+H]⁺.

Step 4.5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

The title compound (0.105 g, 68%) was prepared from the product of Step3 as described in Example 4 Step 3; MS(AP+) m/e 432 [M+H]⁺.

EXAMPLE 8 5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

Step 1.[4-(1-Methoxyimino-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-ylmethyl]-carbamicacid tert-butyl ester

The title compound (1.04 g, 70%) was prepared from the product ofExample 1 Step 4 and (2-oxo-ethyl)-carbamic acid tert-butyl ester asdescribed in Example 1 Step 5; MS(AP+) m/e 434 [M+H]⁺.

Step 2. 5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

The title compound (0.21 g, 30%) was prepared from the product of Step 1as described in Example 1 Step 6; MS(AP+) m/e 305 [M+H]⁺.

Step 3. 5-(2-Aminomethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

The title compound (0.064 g, 80%) was prepared from the product of Step2 as described in Example 4 Step 3; MS(AP+) m/e 320 [M+H]⁺.

EXAMPLE 9 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide

Step 1. 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid[4-(1-oxo-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide

The title compound (0.095 g, 67%) was prepared from the product ofExample 8 Step 2 and 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acidhydrochloride [WO 97/25309] as described in Example 3 Step 1; MS(AP+)m/e 474 [M+H]⁺.

Step 2. 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide

The title compound (0.041 g, 42%) was prepared from the product of Step1 as described in Example 4 Step 3; MS(AP+) m/e 531 [M+H]⁺.

EXAMPLE 105-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

Step 1.5-[2-(1,1-Dimethoxy-methyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneO-methyl oxime

The title compound (1.05 g, 79%) was prepared from the product ofExample 1 Step 4 and dimethoxy-acetaldehyde (45% solution in tert-butylmethyl ether) as described in Example 1 Step 5; MS(AP+) m/e 379 [M+H]⁺.

Step 2. 4-(1-oxo-indan-5-yl)-5-pyridin-4-yl-1H-imidazole-2-carbaldehyde

The title compound (0.92 g, 90%) was prepared from the product of Step 1as described in Example 1 Step 6; MS(AP+) m/e 303 [M+H]⁺.

Step 3.5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

The title compound (0.11 g, 44%) was prepared from the product of Step 2and piperidine as described in Example 6; MS(AP+) m/e 373 [M+H]⁺.

Step 4.5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

The title compound (0.55 g, 53%) was prepared from the product of Step 3as described in Example 4 Step 3; MS(AP+) m/e 387 [M+H]⁺.

EXAMPLE 115-(2-morpholin-4-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

The title compound (0.034 g, 13%) was prepared from the product ofExample 10 Step 2 and morpholine according to the procedures describedin Example 10 Steps 3 and 4; MS(AP+) m/e 390 [M+H]⁺.

EXAMPLE 125-(5-Pyridin-4-yl-2-(2,3,5,6-tetrahydro-[1,2′]bipyrazin-4-ylmethyl)-1H-imidazol-4-yl]-indan-1-oneoxime

The title compound (0.038 g, 17%) was prepared from the product ofExample 10 Step 2 and 3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl accordingto the procedures described in Example 10 Steps 3 and 4; MS(AP+) m/e 467[M+H]⁺.

EXAMPLE 135-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

Step 1.4-[4-(1-Oxo-indan-5-yl)-5-pyridin-4-yl-1H-imidazol-2-methyl]piperazine-1-carboxylicacid tert-butyl ester

The title compound (0.35 g, 74%) was prepared from the product ofExample 10 Step 2 and piperazine-1-carboxylic acid tert-butyl ester asdescribed in Example 6; MS(AP+) m/e 474 [M+H]⁺.

Step 2.5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

A solution of the product of Step 1 (0.350 g, 0.74 mmol) indichloromethane (10 ml) and trifluoroacetic acid (5 ml) was stirred atroom temperature for 3 hours. The solution was concentrated and theresidue co-evaporated with dichloromethane. The residue was dissolved inwater (10 ml) and the solution was neutralised with sodium carbonatesolution. The solvent was evaporated in vacuo and the resulting solidwas dried over phosphorus pentoxide to give title compound which wasused in the next step; MS(AP+) m/e 374 [M+H]⁺.

Step 3.5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime

The title compound (0.105 g, 37%) was prepared from the product of Step2 as described in Example 4 Step 3; MS(AP+) m/e 389 [M+H]⁺.

EXAMPLE 145-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one

Step 1: 5-Bromo-indan-1-one O-methyl-oxime

To a solution of 5-bromo-indanone (100 g, 0.474 mol) in ethanol (650 ml)under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) andpyridine (125 ml). The mixture was refluxed for 2.5 hours, cooled toroom temperature and poured into saturated aqueous sodium hydrogencarbonate solution. The mixture was then extracted with ethyl acetateand the organic phase dried (sodium sulphate) and then concentrated invacuo. The crude material was recrystallised from isopropanol to furnishthe title compound, (110 g, 97%), as a brown solid; ¹H NMR (CDCl₃) 7.52(1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz),3.97 (3H, s), 2.99 (2H, m), 2.99 (2H, m), 2.85 (2H, m).

Step 2: 1-Methoxyimino-indan-5-carbaldehyde

To a solution of the product of Step 1 (112 g, 0.46 mol) in THF (1500ml) at −60° C. under argon, was added n-BuLi (325 ml, 0.52 mol) over 1hour. After stirring at −60° C. for 1 hour a solution of DMF (39.7 ml)in THF (50 ml) was added dropwise over 1 hour. The reaction was stirredat −60° C. for 1 hour before being allowed to warm to room temperature.After 1 hour the reaction was quenched with saturated aqueous sodiumhydrogen carbonate solution and extracted into ethyl acetate. Theorganic phase was then dried (sodium sulphate), concentrated in vacuoand the residue purified by silica gel chromatography, to give the titlecompound (57 g, 65%) as a yellow solid; ¹H NMR (CDCl₃) 10.0 (1H, s),7.83-7.73 (3H, m), 4.02 (3H, s), 3.10 (2H, m), 2.92 (2H, m).

Step 3:5-(1,2-Dihydroxy-2-pyridin-4-yl-ethyl)-indan-1-one-O-methyl-oxime

To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine [T.F. Gallagher et al; Bioorg. Med. Chem., 1997, 5, 49] (71.5 g, 0.32 mol)in THF (800 ml) at −50° C. under argon was added LDA (162 ml, 2M inheptane/THF/ethylbenzene, 0.324 mol) over 1 hour. The mixture wasstirred at −40° C. for a further 1 hour before a solution of the productof Step 2 (55 g, 0.29 mol) in THF (600 ml) was added over 1 hour. Thereaction was then allowed to warm to room temperature overnight beforebeing quenched by the addition of saturated aqueous sodium hydrogencarbonate solution and then extracted into ethyl acetate. The organicphase was dried (sodium sulphate) and concentrated in vacuo to give abrown oil (125 g).

The oil was then dissolved in THF (1500 ml), treated with TBAF (356 ml,0.356 mol) and stirred for 1 hour. The reaction mixture was thenevaporated and the residue partitioned between water and ethyl acetate.The organic phase was then dried (sodium sulphate) and concentrated togive the title compound (57 g, 64%) as a pale yellow solid which wasused without further purification. ¹H NMR (CDCl₃) 8.38 (2H, m), 7.57(1H, m), 7.12-6.99 (4H, m), 4.88 (1H, m), 4.66 (1H, m), 3.96 (3H, s),2.93 (2H, m), 2.85 (2H, m).

Step 4: 1-(1-Methoxyimino-indan-5-yl)-2-pyridin-4-yl-ethane-1,2-dione

To a mixture of DMSO (43 ml, 0.56 mol) and dichloromethane (800 ml) at−70° C. under argon, was added oxalyl chloride (43.2 g) and then asolution of the product of Step 3 (55 g, 0.185 mol) in a mixture ofdichloromethane/DMSO (1000 ml/60 ml) over 2 hours at −60° C. Afterstirring for 2 hours at −60° C., triethylamine (154 ml) was addeddropwise and the mixture then allowed to warm to room temperatureovernight. The reaction mixture was then quenched with water, theorganic phase separated then washed with water, dried (sodium sulphate)and concentrated to yield the title compound (51 g, 94%) as a yellowsolid. ¹H NMR (CDCl₃) 8.87 (2H, d), 7.89-7.77 (5H, m), 4.03 (3H, s),3.09 (2H, m), 2.93 (2H, m).

Step 5:5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-phenyl-1H-imidazol-4-yl}-indan-1-oneO-methyl-oxime

A mixture of the product of Step 4 (0.3 g, 1.02 mmol),4-(3-dimethylamino-propyloxy)-benzaldehyde (0.27 ml, 1.33 mmol) andammonium acetate (0.785 g, 10.2 mmol) in acetic acid (10 ml) was heatedto 100° C. for 1 hour. The reaction was then cooled to room temperature,poured into ice/0.880 ammonia solution and extracted with ethyl acetate.The organic extract was then dried (magnesium sulphate), concentrated invacuo and the crude material purified by silica gel chromatographyeluting with a 1:9:90 mixture of 0.88 ammonia solution:methanol:ethylacetate to give the title compound (0.08 g, 16%) as a yellow solid;MS(AP+) m/e 483 [M+H]⁺.

Step 6:5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one

A mixture of the product of Step 5 (0.07 g, 0.146 mmol) and 5M HCl (4ml) in dioxan (3 ml) was heated to 100° C. for 1 hour. Acetone (3 ml)was then added and the heating continued for a further 1.5 hours beforethe mixture was cooled to room temperature, neutralised with 1 M sodiumhydroxide solution and extracted with ethyl acetate. The organic extractwas then washed with water, dried (magnesium sulphate), concentrated invacuo and the crude material purified by silica gel chromatography,eluting with a 2:18:80 mixture of 0.88 ammonia solution:methanol:ethylacetate to give the title compound (0.035 g, 53%) as a yellow solid;MS(AP+) m/e 453 [M+H]⁺.

EXAMPLE 155-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

Step 1:5-{2-[4-(3-Dimethylamino-propyloxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

To a solution of the product of Example 14, Step 6 (0.07 g, 0.155 mmol)in ethanol (3 ml) at 80° C. was added aqueous hydroxylamine (1.5 ml, 50%in water). After 30 minutes the mixture was cooled to room temperatureand concentrated in vacuo to give the title compound, (0.072 g, 100%) asa yellow solid; MS(AP+) m/e 468 [M+H]⁺.

EXAMPLE 165-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-1-indanone

Step 1:5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one-O-methyl-oxime

The title compound (0.19 g, 30%) was prepared from the product ofExample 14 Step 4 and 4-(2-dimethylamino-ethoxy)-benzaldehyde [WO99/19293] as described in Example 14 Step 5; MS(AP+) m/e 468 [M+H]⁺.

Step 2:5-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-1-indanone

The title compound (0.313 g, 56%) was prepared from the product of Step1 as described in Example 14 Step 6; MS(AP+) m/e 439 [M+H]⁺.

EXAMPLE 175-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

Step 15-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

The title compound (0.321 g, 100%) was prepared from the product ofExample 16 Step 2 as described in Example 15 Step 1; MS(AP+) m/e 454[M+H]⁺.

EXAMPLE 185-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one

Step 1:5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one-O-methyl-oxime

The title compound (0.15 g, 20%) was prepared from the product ofExample 14 Step 4 and 4-(2-morpholin-4-yl-ethoxy)-benzaldehyde [WO96/28448] as described in Example 14 Step 5; MS(AP+) m/e 510 [M+H]⁺

Step 2:5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-one

The title compound (0.048 g, 36%) was prepared from the product of Step1 as described in Example 14 Step 6; MS(AP+) m/e 481 [M+H]⁺.

EXAMPLE 195-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

Step 1:5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime

The title compound (0.048 g, 97%) was prepared from the product ofExample 18 Step 2 as described in Example 15 Step 1; MS(AP+) m/e 496[M+H]⁺.

EXAMPLE 205-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one

Step 1:5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one-O-methyl-oxime

The title compound (0.11 g, 28%) was prepared from the product ofExample 14 Step 4 and pyridine-3-carbaldehyde as described in Example 14Step 5; MS(AP+) m/e 382 [M+H]⁺.

Step 2: 5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one

The title compound (0.025 g, 25%) was prepared from the product of Step1 as described in Example 14 Step 6; MS(AP+) m/e 353 [M+H]⁺.

EXAMPLE 215-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one oxime

Step 1: 5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-oneoxime

The title compound (0.075 g, 76%) was prepared from the product ofExample 20 Step 2 as described in Example 15 Step 1; MS(AP+) m/e368[M+H]⁺.

EXAMPLE 22 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

Step 1:4-[2-Phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine

4-(2-Phenyl-1H-imidazol-4-yl)-pyridine [N. J. Liverton et. al., J. Med.Chem., 1999, 42, 2180] (17.8 g, 80.5 mmol) was dissolved in DMF (150 ml)and cooled to 0° C. The solution was then treated with sodium hydride(3.54 g, 60% dispersion, 88.6 mmol), and stirred for 25 minutesmaintaining the temperature of 0° C.

2-(Trimethylsilyl)ethoxymethyl chloride (14.77 g, 88.6 mmol) was thenadded dropwise over 5 minutes and the mixture warmed to room temperatureovernight. The reaction was then poured into a saturated solution ofsodium hydrogen carbonate and extracted several times with diethylether. The combined ether extracts were then dried (sodium sulphate),concentrated in vacuo and the residue purified by silica gelchromatography, eluting with ethyl acetate to give the title compound asa pale yellow solid (16.8 g, 59%); MS(AP+) m/e 353 [M+H]⁺.

Step 2:4-[5-Bromo-2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine

To a solution of the product of Step 1 (15 g, 42.6 mmol) indichloromethane (300 ml) at room temperature was added bromine (6.81 g,2.38 ml, 46.5 mmol) followed by a saturated solution of sodium carbonate(150 ml). The mixture was stirred for 40 minutes before being separatedand the organic layer washed successively with water and brine. Theorganic layer was then dried (magnesium sulphate) and concentrated invacuo to give the title compound (18. 1 g, 99%) as a brown viscous oilwhich was used without further purification; MS(AP+) m/e 431/433 [M+H]⁺.

Step 3:4-[2-Phenyl-5-tributylstannanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine

To a solution of the product of Step 2 (13.4 g, 31.2 mmol) in THF (200ml) at −78° C. was added dropwise ^(t)BuLi (22 ml, 1.7M, 38 mmol). After25 minutes tributyltin chloride (12.37 g, 10.3 ml, 38 mmol) was addeddropwise and the mixture was then allowed to reach room temperatureovernight. The reaction was then poured into a saturated solution ofsodium hydrogen carbonate and washed several times with diethyl ether.The combined organic layers were dried (magnesium sulphate),concentrated in vacuo and the residue purified by silica gelchromatography, eluting with a 0.5:4.5:45:50 mixture of 0.88 ammoniasolution:methanol:hexane:diethyl ether to give the title compound (18.5g, 93%) as a brown viscous oil; MS(AP+) m/e 641/643/644[M+H]⁺.

Step 4:5-[2-Phenyl-5-pyridin-4-yl-3-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-indan-1-one

Palladium acetate (0.025 g, 0.11 mmol) and triphenylphosphine (0.06 g,0.22 mmol) were suspended in toluene (1 ml). 5-bromoindanone (240 mg, 11mmol) was then added and the mixture heated to 100° C. for 5 min. Thesolution was then treated with a solution of the product of Step 3 (0.6g, 0.94 mmol) in toluene (1 ml) and stirred for 18 hours at 100° C.After cooling the solvent was removed in vacuo and the residue purifiedby silica gel chromatography, eluting with ethyl acetate to afford thetitle compound (0.25 g, 55%) as a yellow solid; MS(AP+) m/e 482 [M+H]⁺.

Step 5: 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one

The product of Step 4 (0.32 g, 0.66 mmol) was dissolved in ethanol (4ml), 5M aqueous hydrochloric acid solution (3 ml) added and the mixtureheated to reflux for 30 min. On cooling, the solvent was removed invacuo to afford the title compound as a yellow solid (0.27 g, 96%);MS(AP+) m/e 352 [M+H]⁺.

EXAMPLE 23 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime

Step 1: 5-(2-Phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime

A solution of the product of Example 22 Step 5 (0.06 g, 0.17 mmol) andhydroxylamine hydrochloride (0.035 g, 0.5 mmol) in 40% aqueous sodiumhydroxide (2 ml) and ethanol (3 ml) was heated to reflux for 30 min. Oncooling the mixture was neutralised with aqueous 2M hydrochloric acidand extracted into ethyl acetate. The organic layer was washed withbrine, dried (magnesium sulphate) and concentrated in vacuo. The residuewas purified by silica gel chromatography eluting with a 1:9:90 mixtureof 0.88 ammonia solution:methanol:dichloromethane to give the titlecompound (0.05 g, 80%) as a yellow solid; MS(AP+) m/e 367 [M+H]⁺.

BIOLOGICAL EXAMPLES

The activity of compounds of formula (I) as B-Raf inhibitors may bedetermined by the following in vitro assays:

Fluorescence Anisotropy Kinase Binding Assay

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×K_(i)) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be >1×K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration. A typical protocol is:

All components dissolved in Buffer of composition 50 mM HEPES, pH 7.5, 1mM CHAPS, 10 mM MgCL₂.

B-Raf Enzyme concentration: 1 nM

Fluorescent ligand concentration: 0.5 nM

Test compound concentration: 0.1 nM-100 uM

Components incubated in 10 ul final volume in LJL HE 384 type B blackmicrotitre plate until equilibrium reached (Over 3 h, up to 30 h)

Fluorescence anisotropy read in LJL Acquest.

-   Definitions: K_(i)=dissociation constant for inhibitor binding    -   K_(f)=dissociation constant for fluorescent ligand binding

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Raf Kinase Assay

Activity of human recombinant B-Raf protein was assessed in vitro byassay of the incorporation of radiolabelled phosphate to recombinant MAPkinase (MEK), a known physiologic substrate of B-Raf. Catalyticallyactive human recombinant B-Raf protein was obtained by purification fromsf9 insect cells infected with a human B-Raf recombinant baculovirusexpression vector. To ensure that all substrate phosphorylation resultedfrom B-Raf activity, a catalytically inactive form of MEK was utilised.This protein was purified from bacterial cells expression mutantinactive MEK as a fusion protein with glutathione-S-transferase(GST-kdMEK).

Method: Standard assay conditions of B-Raf catalytic activity utilised 3ug of GST-kdMEK, 10 uM ATP and 2 uCi ³³P-ATP, 50 mM MOPS, 0.1 mM EDTA,0.1M sucrose, 10 mM MgCl₂ plus 0.1% dimethylsulphoxide (containingcompound where appropriate) in a total reaction volume of 30 ul.Reactions were incubated at 25° C. for 90 minutes and reactionsterminated by addition of EDTA to a final concentration of 50 uM. 10 ulof reaction was spotted to P30 phosphocellulose paper and air dried.Following four washes in ice cold 10% trichloroacetic acid, 0.5%phosphoric acid, papers were air dried prior to addition of liquidscintillant and measurement of radioactvity in a scintillation counter.

Results: The compounds of the examples were found to be effective ininhibiting B-Raf mediated phosphorylation of GST-kdMEK substrate havingIC₅₀'s of <3 μM.

The activity of compounds as Raf inhibitors may also be determined bythe assays described in WO 99/10325; McDonald, O. B., Chen, W. J.,Ellis, B., Hoffman, C., Overton, L., Rink, M., Smith, A., Marshall, C.J. and Wood, E. R. (1999) A scintillation proximity assay for theRaf/MEK/ERK kinase cascade: high throughput screening and identificationof selective enzyme inhibitors, Anal. Biochem. 268: 318-329 and AACRmeeting New Orleans 1998 Poster 3793.

The neuroprotective properties of B-Raf inhibitors may be determined bythe following in vitro assay:

Neuroprotective Properties of B-Raf Inhibitors in Rat Hippocampal SliceCultures

Organotypic cultures provide an intermediate between dissociatedneuronal cell cultures and in-vivo models of oxygen and glucosedeprivation (OGD). The majority of glial-neuronal interactions andneuronal circuitry are maintained in cultured hippocampal slices, sofacilitating investigation of the patterns of death among differing celltypes in a model that resembles the in vivo situation. These culturesallow the study of delayed cellular damage and death 24 hours, or more,post-insult and permit assessment of the consequences of long-termalterations in culture conditions. A number of laboratories havereported delayed neuronal damage in response to OGD in organotypiccultures of the hippocampus (Vornov et al, Stroke, 1994, 25, 57-465;Newell et al., Brain Res., 1995, 676, 38-44). Several classes ofcompounds have been shown to protect in this model, including EAAantagonists (Strasser et al., Brain Res., 1995, 687, 167-174), Nachannel blockers (Tasker et al., J. Neurosci., 1992, 12, 98-4308) and Cachannel blockers (Pringle et al., Stroke, 1996, 7, 2124-2130). To date,relatively little is known of the roles of intracellular kinase mediatedsignalling pathways in neuronal cell death in this model.

Method: Organotypic hippocampal slice cultures were prepared using themethod of Stoppini et al., J. Neurosci. Methods, 1995, 37, 173-182.Briefly, 400 micron sections prepared from hippocampi of 7-8 daypostnatal Sprague Dawley rats are cultured on semiporous membranes for9-12 days. OGD is then induced by incubation in serum and glucose-freemedium in an anaerobic chamber for 45 minutes. Cultures are thenreturned to the air/CO₂ incubator for 23 hours before analysis.Propidium iodide (PI) is used as an indicator of cell death. PI is nontoxic to neurones and has been used in many studies to ascertain cellviability. In damaged neurons PI enters and binds to nucleic acids.Bound PI shows increased emission at 635 nm when excited at 540 nm. OnePI fluorescence image and one white light image are taken and theproportion of cell death analysed. The area of region CA1 is definedfrom the white light image and superimposed over the PI image. The PIsignal is thresholded and area of PI damage expressed as a percentage ofthe CA1 area. Correlation between PI fluorescence and histologicallyconfirmed cell death has been validated previously by Nissl-stainingusing cresyl fast violet (Newell et al., J. Neurosci., 1995, 15,7702-771 1).

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofcomposition, process, or use claims and may include by way of exampleand without limitation the following claims.

1. A compound of formula (I):

wherein X is O, CH₂, CO, S or NH, or the moiety X—R¹ is hydrogen; Y₁ andY₂ are independently N or CH; R¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,aryl, arylC₁₋₆alkyl, heterocyclyl, heterocyclylC₁₋₆alkyl, heteroaryl, orheteroarylC₁₋₆alkyl, any of which may be optionally substituted; inaddition when X is CH₂ then R¹ may be hydroxy or C₁₋₆alkoxy which may beoptionally substituted; R² is a substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl aryl, wherein the substituent isselected from aryl, heteroaryl, heterocyclyl, C₁₋₆alkoxy, C₁₋₆alkylthio,arylC₁₋₆alkoxy, aryl C₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino,aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy and esters thereof,amide, ureido, guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino,C₁₋₆acyloxy, hydroxy, and halogen or any combinations thereof but mustinclude a heterocyclyl or heteroaryl group, or R² is a heterocyclyl, orheteroaryl, either of which may be optionally substituted; Ar is a groupof the formula a) or b):

 wherein A represents a fused 5- to 7-membered ring optionallycontaining up to two heteroatoms selected from O, S and NR⁵, wherein R⁵is hydrogen or C₁₋₆alkyl, which ring is optionally substituted by up to2 substituents selected from halogen, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy orketo; R³ and R⁴ are independently selected from hydrogen, halogen,C₁₋₆alkyl, aryl, aryl C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,haloC₁₋₆alkyl, arylC₁₋₆alkoxy, hydroxy, nitro, cyano, azido, amino,mono- and di-N—C₁₋₆alkylamino, acylamino, arylcarbonylamino, acyloxy,carboxy, carboxy salts, carboxy esters, carbamoyl, mono- anddi-N—C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino,sulphonylamino, aminosulphonyl, C₁₋₆alkylthio, C₁₋₆alkylsulphinyl orC₁₋₆alkylsulphonyl; R¹⁵ is O or N—OH; one of X₁ and X₂ is N and theother is NR⁶ wherein R⁶ is hydrogen or C₁₋₆alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of formula (I) according to claim1 wherein X is NH or X—R¹ is hydrogen.
 3. A compound of formula (I)according to claim 1 wherein R¹⁵ is N—OH
 4. A compound of formula (I)according to claim 1 wherein R² is i) —CR⁷R⁸—CH₂-Z, —CH₂-Z andheterocyclyl, wherein R⁷ and R⁸ independently represent hydrogen oroptionally substituted C₁₋₆alkyl, or R⁷ and R⁸ together with the carbonatom to which they are attached form an optionally substitutedC₃₋₇cycloalkyl or C₅₋₇cycloalkenyl ring; and Z is NR⁹R¹⁰, NR⁹C(Q)NR⁹R¹⁰,NR⁹COOR¹⁰, NR⁹SO₂R¹⁰, NR⁹C(Q)R¹⁰ or heterocyclyl wherein R⁹ and R¹⁰ areindependently selected from heterocyclyl, heterocyclylC₁₋₆alkyl,heteroaryl and heteroarylC₁₋₆alkyl, any of which may be optionallysubstituted or together form a heterocyclic group, when present asNR⁹R¹⁰; Q is O or S, preferably O; and when R² or Z is heterocyclyl,e.g. piperidyl, piperazine or morpholine, the heterocyclyl group isoptionally substituted; or ii) optionally substituted pyridyl, pyrimidyland furanyl.
 5. A compound of formula (I) according to claim 1 whereinR³ is hydrogen.
 6. A compound of formula (I) according to claim 1wherein R⁴ is hydrogen.
 7. A compound of formula (I) according to claim1 wherein R⁶ is hydrogen.
 8. A compound of formula (I) according toclaim 1 which is selected from:1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid{2-[5-(1-hydroxyimino-indan-5-yl)-4-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide;5-(2-Piperidin-4-yl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-one oxime;5-[2-(1-{1-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-mathanoyl}-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime;5-[2-(1-Furan-3-ylmethyl-piperidin-4-yl)-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime;5-{2-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-5-pyridin-4-yl-1H-imidazol-4-yl}-indan-1-oneoxime; 1-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl)-1H-imidazol-2-ylmethyl]-amide;5-(2-Piperidin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime5-(2-Morpholin-4-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl)-indan-1-oneoxime;5-(5-Pyridin-4-yl-2-(2,3,5,6-tetrahydro-[1,2′]bipyrazin-4-ylmethyl)-1H-imidazol-4-yl]-indan-1-oneoxime;5-(2-Piperazin-1-ylmethyl-5-pyridin-4-yl-1H-imidazol-4-yl]-indan-1-oneoxime;5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl1-indan-1-one;5-{2-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl}1-indan-1-oneoxime; 5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl)-indan-1-one;5-(5-Pyridin-4-yl-2-pyridin-3-yl-1H-imidazol-4-yl}-indan-1-one oxime;and pharmaceutically acceptable salts thereof.
 9. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. Amethod of therapeutic treatment of any disease state in a human, orother mammal, which is exacerbated or caused by a neurotraumatic eventwhich method comprises administering to a human or other mammal atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.
 14. A method of therapeutictreatment of ischemic stroke which method comprises administering to ahuman or other mammal a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.
 15. Amethod of therapeutic treatment of cancer which method comprisesadministering to a human or other mammal a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.
 16. A method of therapeutic treatment of chronicneurogeneration, pain, migraine and cardiac hypertrophy which methodcomprises administering to a human or other mammal a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.
 17. A method of therapeutic treatment of anydisease state in a human, or other mammal, which is exacerbated orcaused by a neurotraumatic event which method comprises administering toa human or other mammal a therapeutically effective amount of a compoundof formula (Ia)

wherein X is O, CH₂, CO, S or NH, or the moiety X—R¹ is hydrogen; Y₁ andY₂ are CH; R¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, orarylC₁₋₆alkyl, any of which may be optionally substituted; in addition,when X is CH₂ then R¹ may be hydroxy or C₁₋₆alkoxy which may beoptionally substituted; R² is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl,C₅₋₇cycloalkenyl, or aryl, any of which may be optionally substituted;Ar is a group of the formula a) or b):

 wherein A represents a fused 5-membered carbocyclic ring which ring isoptionally substituted by up to 2 substituents selected from halogen,C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy and keto; R³ and R⁴ are independentlyselected from hydrogen, halogen, C₁₋₆alkyl, aryl, aryl C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, haloC₁₋₆alkyl, arylC₁₋₆alkoxy, hydroxy,nitro, cyano, azido, amino, mono- and di-N—C₁₋₆alkylamino, acylamino,arylcarbonylamino, acyloxy, carboxy, carboxy salts, carbamoyl, mono- anddi-N—C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino,sulphonylamino, aminosulphonyl, C₁₋₆alkylthio, C₁₋₆alkylsulphinyl andC₁₋₆alkylsulphonyl; R¹⁵ is O or N—OH; one of X₁ and X₂ is N and theother is NR⁶ wherein R⁶ is hydrogen or C₁₋₆alkyl; wherein the optionalsubstituents for alkyl, alkoxy, alkenyl, cycloalkyl and cycloalkenylgroups are selected from aryl, C₁₋₆alkoxy, C₁₋₆alkylthio,arylC₁₋₆alkoxy, aryl C₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino,aminosulphonyl, cycloalkyl, cycloalkenyl, carboxy, amide, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino, C₁₋₆acyloxy,hydroxy, halogen, cyano and any combinations thereof; wherein the arylgroups may be optionally substituted by a substituent selected fromhalogen, hydroxy, C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, haloC₁₋₆alkyl, arylC₁₋₆alkoxy, nitro, cyano, azido,amino, mono- and di-N—C₁₋₆alkylamino, acylamino, arylcarbonylamino,acyloxy, carboxy, carboxy salts, carbamoyl, mono- anddi-N—C₁₋₆alkylcarbamoyl, C₁₋₆alkoxycarbonyl, aryloxycarbonyl, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino, urea,carbamate, acyl, sulphonylamino, aminosulphonyl, C₁₋₆alkylthio,C₁₋₆alkylsulphinyl, C₁₋₆alkylsulphonyl, and any combination thereof; ora pharmaceutically acceptable salt thereof.
 18. A method of therapeutictreatment of ischemic stroke which method comprises administering to ahuman or other mammal a therapeutically effective amount of a compoundof formula (Ia) as defined in claim 17 or a pharmaceutically acceptablesalt thereof.
 19. A method of therapeutic treatment of cancer whichmethod comprises administering to a human or other mammal atherapeutically effective amount of a compound of formula (Ia) asdefined in claim 17 or a pharmaceutically acceptable salt thereof.
 20. Amethod of therapeutic treatment of chronic neurogeneration, pain,migraine and cardiac hypertrophy which method comprises administering toa human or other mammal a therapeutically effective amount of a compoundof formula (Ia) as defined in claim 17 or a pharmaceutically acceptablesalt thereof.